Novel polymorphs of quetiapine fumarate

ABSTRACT

The present invention relates to novel polymorphic forms of quetiapine fumarate, processes for their preparation and pharmaceutical compositions containing them.

FIELD OF THE INVENTION

[0001] The present invention relates to novel polymorphic forms ofquetiapine fumarate, processes for their preparation and pharmaceuticalcompositions containing them.

BACKGROUND OF THE INVENTION

[0002]2-[2-(4-Dibenzo[b,f]-[1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol(quetiapine) and its salts were disclosed in Eur. Pat. No. 0240228 andthey are useful for their antidopaminergic activity, for example, as anantipsychotic or neuroleptic.

[0003] Various processes for preparation of quetiapine and2-[2-(4-Dibenzo[b,f]-[1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanolhemifumarate (quetiapine fumarate) were described in EP 0240 228, EP0282236, WO 01/55125 and WO 99/06381. According to the teachings ofliterature, quetiapine fumarate was crystallized from ethanolic solutioncontaining quetiapine free base and fumaric acid. Quetiapine fumarateprepared according this method fails to produce well definedreproducible crystalline form.

[0004] It has now been discovered stable, reproducible two crystallineforms of quetiapine fumarate. It has also been discovered that thecrystalline forms of quetiapine fumarate can be obtained in very purestate. Thus, they can be used as active ingredients in pharmaceuticalpreparations.

[0005] Thus, the object of the present invention is to providequetiapine fumarate in stable and reproducible crystalline forms,processes for their preparation and pharmaceutical compositioncontaining them.

[0006] The present invention also provides amorphous form of quetiapinewith adequate stability and good dissolution properties.

[0007] Thus another object of the present invention is to provideamorphous form of quetiapine fumarate, a process for preparing it and apharmaceutical composition containing it.

DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention provides a novel crystalline form ofquetiapine fumarate, which is designated as form I. Quetiapine fumaratecrystalline Form I is characterized by x-ray powder diffraction patternhaving significant reflections expressed as 2θ values at about 7.3, 9.2,11.6, 13.3, 14.4, 14.8, 15.3, 15.9, 16.2, 16.7, 17.6, 19.1, 19.7, 20.1,20.8, 21.1, 21.8, 22.3, 23.4, 24.3, 24.7, 25.1, 25.6, 27.1, 28.5, 29.5,33.2, 40.4 deg.

[0009] x-Ray powder diffractogram of quetiapine fumarate crystallineForm I is shown in FIG. 1 . The major peaks and their intensities ofx-ray powder diffractogram are shown in Table 1. The intensities of thereflections are expressed as percent of most intense reflection.

[0010] A further aspect of the present invention provides a process forthe preparation of quetiapine fumarate crystalline Form I.

[0011] Quetiapine fumarate crystalline Form I is prepared by dissolvingquetiapine free base and fumaric acid in a suitable solvent andcrystallizing fumarate salt. This crystallization from the suitablesolvent is an effective method of removing impurities.

[0012] A further aspect of the present invention thus providesquetiapine fumarate crystalline Form I which is substantially pure, forexample at least 98 % preferably at least 99%, more preferably at least99.5% pure.

[0013] Preferably molar ratio of quetiapine free base to fumaric acid isbetween about 1:0.4 to about 1:1.

[0014] The suitable solvents are ketones like acetone, methyl iso butylketone; esters like ethyl acetate, ethyl formate, methyl acetate; andmixture thereof.

[0015] The preparation of quetiapine free base is described, for examplein EP 0240228.

[0016] Crystallization of quetiapine fumarate from solution may beinitiated by conventional means such as addition of a non-solvent,evaporation of solvent, cooling or seeding the solution.

[0017] The present invention also provides another novel crystallineform of quetiapine fumarate, which is designated as Form II. Quetiapinefumarate crystalline Form II is characterized by x-ray powderdiffraction pattern having significant reflections expressed as 20values at about 4.9, 7.4, 9.2, 11.7, 13.4, 14.4, 14.9, 15.4, 15.9, 16.3,16.7, 17.7, 18.6, 19.8, 20.2, 20.8, 21.2, 21.9, 22.4, 22.9, 23.4, 24.3,24.7, 25.2, 25.7, 26.9, 27.8, 28.8, 29.4, 33.2, 35.9, 38.0, 38.7, 39.9,42.8 deg.

[0018] x-Ray powder diffractogram of quetiapine fumarate Form II isshown in FIG. 2. The major peaks and their intensities of x-ray powderdiffractogram are shown in table 2. The intensities of the peaks areexpressed as percent of most intense reflection.

[0019] A further aspect of the present invention provides a process forthe preparation of quetiapine fumarte Form II.

[0020] Quetiapine fumarate crystalline Form II is prepared by dissolvingquetiapine free base in methyl tert. butyl ether, heating to reflux,adding fumaric acid at reflux, maintaining at reflux for about 30minutes to about 1 hour, cooling to 20-30° C., maintaining for about 30minutes with or without stirring, optionally seeding with quetiapinefumarate crystalline Form II, filtering and washing the crystals formedwith methyl tert. butyl ether.

[0021] Preferably molar ratio of quetiapine free base to fumaric acid isbetween about 1:0.4 to about 1:1.

[0022] The present invention also provides a novel amorphous form ofquetiapine fumarate, which is designated as amorphous quetiapinefumarate. The amorphous quetiapine fumarate is characterized by havingbroad x-ray diffraction maximum expressed as 2θ between about 10 andabout 30 deg.

[0023] A further aspect of the present invention provides a process forthe preparation of amorphous quetiapine fumarate. Amorphous quetiapinefumarate may be prepared by dissolving quetiapine fumarate in a solventmixture, removing the solvent from the solution. Quetiapine fumaratecrystalline Form I or Form II, which are obtained as described hereinabove, or quetiapine fumarate obtained by previously known methods maybe used for the preparation of amorphous quetiapine fumarate.

[0024] The solvent mixture comprises chloroform and methanol in a ratiobetween about 1:0.5 and 1:2 volume/volume, preferably in the ratio of1:1 volume/volume. The solvent can be removed form the solution bytechniques such as vacuum drying or spray drying.

[0025] A further aspect of the present invention provides apharmaceutical composition comprising an effective amount of quetiapinefumarate polymorphic form and a pharmaceutically acceptable carrier.

[0026] The quetiapine fumarate polymorphic forms include quetiapinefumarate crystalline Form I, quetiapine fumarate crystalline Form II andamorphous quetiapine fumarate.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027]FIG. 1 is x-ray powder diffraction pattern of quetiapine fumaratecrystalline Form I.

[0028]FIG. 2 is x-ray powder diffraction pattern of quetiapine fumaratecrystalline Form II.

[0029]FIG. 3 is x-ray powder diffractogram of amorphous quetiapinefumarate.

[0030] The x-ray powder diffraction spectra was measured on a SiemensD-5000 diffractometer. TABLE 1 2θ (degree) % Intensity 7.3 30.4 9.2 39.911.6 39.3 13.3 33.1 14.4 12.9 14.8 27.1 15.3 42.2 15.9 16.8 16.2 83.316.7 39.0 17.6 41.6 19.1 13.4 19.7 48.1 20.1 100.0 20.8 30.8 21.1 91.821.8 43.3 22.3 57.2 23.4 57.2 24.3 21.7 24.7 13.8 25.1 32.6 25.6 28.927.1 13.7 28.5 20.4 29.5 13.0 33.2 26.3 40.4 13.0

[0031] TABLE 2 2θ (degree) % Intensity 4.9 9.9 7.4 24.0 9.2 41.0 11.737.7 13.4 25.5 14.4 22.2 14.9 32.0 15.4 33.2 15.9 25.2 16.3 52.5 16.736.4 17.7 28.4 18.6 22.3 19.8 53.1 20.2 82.2 20.8 24.7 21.2 77.3 21.941.8 22.4 43.6 22.9 100.0 23.4 49.5 24.3 20.2 24.7 20.4 25.2 24.7 25.738.5 26.9 25.4 27.8 20.2 28.8 80.8 29.4 53.2 33.2 23.8 35.9 11.8 38.028.7 38.7 24.9 39.9 13.8 42.8 14.3

[0032] The following examples are presented for illustrative purposesonly and are not intended as a restriction on the scope of theinvention.

EXAMPLE 1

[0033] Quetiapine free base (5 gm) obtained by the process described inEP 0240228 (example 1) is dissolved in acetone (60 ml). To thissolution, fumaric acid (0.9 gm) is added and then heated for completedissolution. The solution is cooled to 20 to 25° C. and maintained for 1hour. The product obtained is filtered washed with acetone and dried togive 4.9 gm of quetiapine fumarate Form I. (HPLC purity: 99.8%).

EXAMPLE 2

[0034] Example 1 is repeated using 60 ml ethyl acetate instead ofacetone. Yield of quetiapine fumarate Form I is 5.2 gm (HPLC purity:99.6%).

EXAMPLE 3

[0035] Example 1 is repeated by seeding the solution with quetiapinefumarate Form 1 during maintenance at 20 to 25° C. Yield of quetiapinefumarate Form I is 5.2 gm (HPLC purity: 99.8%).

EXAMPLE 4

[0036] Quetiapine free base (10 gm), obtained by the process describedin example 1 of EP 0240228 is dissolved in methyl tert. butyl ether (100ml). The solution is heated to reflux and fumaric acid (1.5 gm) is addedat reflux. The refluxing is continued for 45 minutes, cooled to 20-25°C. and stirred for 30 minutes. The resulting crystals are filteredwashed with methyl tert. butyl ether and dried to give 19.2 gm ofquetiapine fumarate Form II.

EXAMPLE 5

[0037] Example 4 is repeated by seeding the contents during maintenanceat 20 to 25° C. with quetiapine fumarate Form II. The yield ofquetiapine fumarate Form II is 19.5 gm.

EXAMPLE 6

[0038] Quetiapine fumarate (2 gm) obtained by the process described inexample 4 of EP 0240228 added to a solvent mixture containing methanol(10 ml) and chloroform (10 ml). The contents are heated to 40-45° C. fordissolution and the clear solution is subjected to vacuum drying at35-40° C. for 15 to 20 hours to give 1.9 gm of amorphous quetiapinefumarate.

EXAMPLE 7

[0039] Example 6 is repeated using quetiapine fumarate Form I instead ofquetiapine fumarate. The yield of amorphous quetiapine fumarate is 1.8gm.

EXAMPLE 8

[0040] Example 6 is repeated by subjecting the clear solution to spraydrying instead of vacuum drying to give 1.8 gm of amorphous quetiapinefumarate.

1-19. Cancelled 20) Quetiapine fumarate crystalline Form I having anx-ray powder diffractogram havingpeaks expressed as 2θ at about 7.3,9.2, 11.6, 13.3, 14.4, 14.8, 15.3, 15.9, 16.2, 16.7, 17.6, 19.1, 19.7,20.1, 20.8, 21.1, 21.8, 22.3, 23.4, 24.3, 24.7, 25.1, 25.6, 27.1, 28.5,29.5, 33.2, and 40.4 degrees. 21) Quetiapine fumarate crystalline Form Ihaving an x-ray powder diffractogram as shown in FIG.
 1. 22) A processfor preparation of quetiapine fumarate Form I as defined in claim 20,which comprises the steps of: a) dissolving quetiapine free base andfumaric acid in a suitable solvent; and b) crystallizing quetiapinefumarate Form I from the solution formed in step (a). 23) A processaccording to claim 22 wherein the suitable solvent is selected from thegroup consisting of acetone, methyl isobutyl ketone, ethyl acetate,ethyl formate and methyl acetate. 24) A process according to claim 22wherein the suitable solvent is acetone. 25) A process according toclaim 22 wherein the suitable solvent is ethylacetate. 26) A processaccording to claim 22, wherein the crystallization is initiated byseeding with quetiapine fumarate Form I. 27) A process according toclaim 23, wherein the crystallization is initiated by seeding withquetiapine fumarate Form I. 28) Quetiapine fumarate crystalline Form IIhaving an x-ray powder diffractogram having peaks expressed as 2θ atabout 4.9, 7.4, 9.2, 11.7, 13.4, 14.4, 14.9, 15.4, 15.9, 16.3, 16.7,17.7, 18.6, 19.8, 20.2, 20.8, 21.2, 21.9, 22.4, 22.9, 23.4, 24.3, 24.7,25.2, 25.7, 26.9, 27.8, 28.8, 29.4, 33.2, 35.9, 38.0, 38.7, 39.9, and42.8 degrees. 29) Quetiapine fumarate crystalline Form II having anx-ray powder diffractogram as shown in FIG.
 2. 30) A process forpreparation of quetiapine fumarate crystalline Form II as defined inclaim 28, which comprises the steps of dissolving quetiapine free basein methyl tert. butyl ethers, heating to reflux, adding fumaric acid atreflux, maintaining at reflux for about 30 minutes to about 1 hour,cooling to about 20 to 30° C., maintaining for about 30 minutes with orwithout stirring, optionally seeding, and collecting the quetiapinefumarate Form II crystals formed. 31) A process according to claim 30,wherein the solution is seeded with quetiapine fumarate Form II. 32)Amorphous quetiapine fumarate having an x-ray powder diffractogramhaving a maximum expressed as 20 at about 10 to about 30 degrees. 33)Amorphous quetiapine fumarate having an x-ray powder diffractogram asshown in FIG.
 3. 34) A process for preparation of amorphous quetiapinefumarate as defined in claim 32, which comprises the steps of: a)dissolving quetiapine fumarate in a solvent mixture of chloroform andmethanol; and b) removing the solvents from the solution formed in step(a) by drying. 35) A process according to claim 34, wherein the solventsare removed by vacuum drying. 36) A process according to claim 34,wherein the solvents are removed by spray drying. 37) A pharmaceuticalcomposition comprising a quetiapine fumarate polymorphic form and apharmaceutically acceptable carrier. 38) A pharmaceutical compositionaccording to claim 37, wherein the quetiapine fumarate polymorphic formis quetiapine fumarate crystalline Form I. 39) A pharmaceuticalcomposition according to claim 37, wherein the quetiapine fumaratepolymorphic form is quetiapine fumarate crystalline Form II. 40) Apharmaceutical composition according to claim 37, wherein the quetiapinefumarate polymorphic form is amorphous quetiapine fumarate.